Substituted 5-aminomethyl-1H-pyrrole-2-carboxamides

ABSTRACT

5-aminomethyl-1H-pyrrole-2-carboxylic acid amide compounds corresponding to formula I  
                 
and processes for the production thereof. Pharmaceutical preparations containing these compounds and the use of these compounds for the production of pharmaceutical preparations and in related treatment methods.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Patent ApplicationNo. PCT/EP2003/014496, filed Dec. 18, 2003, designating the UnitedStates of America, and published in German as WO 2004/058707 A1, theentire disclosure of which is incorporated herein by reference. Priorityis claimed based on German Patent Application No. 102 61 131.9, filedDec. 20, 2002.

FIELD OF THE INVENTION

The present invention relates to substituted5-aminomethyl-1H-pyrrole-2-carboxylic acid amides, to a process for theproduction thereof, to pharmaceutical preparations containing thesecompounds and to the use of these compounds for the production ofpharmaceutical preparations and in related treatment methods.

BACKGROUND OF THE INVENTION

Pain is one of the basic clinical symptoms. There is a worldwide needfor effective pain treatments. The urgency of the requirement fortherapeutic methods for providing tailored and targeted treatment ofchronic and non-chronic pain, this being taken to mean pain treatmentwhich is effective and satisfactory from the patient's standpoint, isevident from the large number of scientific papers relating to appliedanalgesia and to basic nociception research which have appeared inrecent times.

Conventional opioids, such as for example morphine, are effective in thetreatment of severe to very severe pain, but they exhibit unwantedaccompanying symptoms, such as for example respiratory depression,vomiting, sedation or constipation. Research is being carried outworldwide into other pain-relieving agents.

SUMMARY OF THE INVENTION

One object of certain embodiments of the present invention is to providenovel active ingredients which are in particular suitable for use inpharmaceutical preparations, preferably in pharmaceutical preparationsfor combating, inhibiting and alleviating pain.

This object is achieved by the substituted5-aminomethyl-1H-pyrrole-2-carboxylic acid amides, according to theinvention, of the general formula I below.

It has surprisingly been found that the substituted5-aminomethyl-1H-pyrrole-2-carboxylic acid amides according to theinvention of the general formula I below exhibit elevated affinity forthe ORL (“opioid receptor like”)-1 receptor as well as for the μ opioidreceptor and are accordingly suitable for regulating these receptors.The substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amidesaccording to the invention of the general formula I below furthermorebring about inhibition of noradrenalin uptake and inhibition of5-hydroxytryptamine (5-HT) uptake.

The substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amidesaccording to the invention of the general formula I below in particularexhibit a marked activity in combatting pain, preferably chronic painand/or acute pain and/or neuropathic pain. The substituted5-aminomethyl-1H-pyrrole-2-carboxylic acid amides according to theinvention are furthermore also suitable for the treatment of withdrawalsymptoms, memory disorders, neurodegenerative diseases, preferablyParkinson's disease, Huntington's chorea or Alzheimer's disease,epilepsy, disorders of the cardiovascular system, water retentionconditions, intestinal motility (diarrhoea), urinary incontinence,anorexia, pruritus, depression, tinnitus, sexual dysfunction, preferablyerectile dysfunction, respiratory diseases, or for diuresis, forinfluencing the cardiovascular system, preferably for vasodilating thearteries, for suppression of the urinary reflex, for anxiolysis, forregulating the electrolyte balance, for regulating, preferablystimulating, food intake, for reducing the addictive potential ofopioids, in particular of morphine, for modulating locomotor activity,for influencing the action of μ agonists, in particular morphine.

The present invention accordingly provides substituted5-aminomethyl-1H-pyrrole-2-carboxylic acid amides of the followinggeneral formula I,

in which

-   R¹ denotes hydrogen, a linear or branched, saturated or unsaturated,    optionally at least mono-substituted aliphatic residue, a saturated    or unsaturated, optionally at least mono-substituted, cycloaliphatic    residue optionally comprising at least one heteroatom as a ring    member and optionally attached via an optionally at least    mono-substituted alkylene group, an optionally at least    mono-substituted aryl or heteroaryl residue or an optionally at    least mono-substituted aryl or heteroaryl residue attached via an    optionally substituted alkylene group,-   R² denotes a linear or branched, saturated or unsaturated,    optionally at least mono-substituted aliphatic residue, a saturated    or unsaturated, optionally at least mono-substituted, cycloaliphatic    residue optionally comprising at least one heteroatom as a ring    member and optionally attached via an optionally at least    mono-substituted alkylene group, an optionally at least    mono-substituted aryl or heteroaryl residue or an optionally at    least mono-substituted aryl or heteroaryl residue attached via an    optionally substituted alkylene group, or-   R¹ and R², together with the nitrogen atom joining them as a ring    member, form a saturated or unsaturated, optionally at least    mono-substituted cycloaliphatic residue optionally comprising at    least one further heteroatom as a ring member,-   R³ denotes an optionally at least mono-substituted aryl or    heteroaryl residue, an ester group or a carboxy group,-   R⁴ and R⁵, identical or different, denote hydrogen, a linear or    branched, saturated or unsaturated, optionally at least    mono-substituted aliphatic residue, a saturated or unsaturated,    optionally at least mono-substituted, cycloaliphatic residue    optionally comprising at least one heteroatom as a ring member and    optionally attached via an optionally at least mono-substituted    alkylene group, an optionally at least mono-substituted aryl or    heteroaryl residue or an optionally at least mono-substituted aryl    or heteroaryl residue attached via an optionally substituted    alkylene group, or-   R⁴ and R⁵, together with the nitrogen atom joining them as a ring    member, form a saturated or unsaturated, optionally at least    mono-substituted cycloaliphatic residue optionally comprising at    least one further heteroatom as a ring member, and-   R⁶ denotes a linear or branched, saturated or unsaturated,    optionally at least mono-substituted aliphatic residue, a saturated    or unsaturated, optionally at least mono-substituted, cycloaliphatic    residue optionally comprising at least one heteroatom as a ring    member and optionally attached via an optionally at least    mono-substituted alkylene group, an optionally at least    mono-substituted aryl or heteroaryl residue or an optionally at    least mono-substituted aryl or heteroaryl residue attached via an    optionally at least mono-substituted alkylene group,-   optionally in the form of the pure stereoisomers thereof, in    particular enantiomers or diastereomers, the racemates thereof or in    the form of mixtures of the stereoisomers, in particular the    enantiomers, diastereomers or rotamers, in any desired mixing ratio,    or in each case in the form of the acids or bases thereof or in the    form of the salts thereof, in particular the physiologically    acceptable salts, or in each case in the form of the solvates    thereof, in particular the hydrates.

Preferred substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amidesaccording to the invention of the general formula I are those in whichR¹ denotes hydrogen, a linear or branched, saturated or unsaturated,optionally at least mono-substituted aliphatic C₁₋₆ residue, a saturatedor unsaturated, optionally at least monosubstituted cycloaliphatic C₃₋₈residue optionally comprising at least one heteroatom as a ring memberand optionally attached via an optionally at least mono-substituted C₁₋₃alkylene group, an optionally at least mono-substituted five- orsix-membered aryl or heteroaryl residue or an optionally at leastmono-substituted, five- or six-membered aryl or heteroaryl residueattached via an optionally substituted C₁₋₃ alkylene group, preferably alinear or branched, saturated aliphatic C₁₋₃ residue, particularlypreferably a methyl residue and the remaining residues R²-R⁶ have theabove-stated meaning, optionally in the form of the pure stereoisomersthereof, in particular enantiomers or diastereomers, the racematesthereof or in the form of mixtures of the stereoisomers, in particularthe enantiomers, diastereomers or rotamers, in any desired mixing ratio,or in each case in the form of the acids or bases thereof or in the formof the salts thereof, in particular the physiologically acceptablesalts, or in each case in the form of the solvates thereof, inparticular the hydrates.

Likewise preferred substituted 5-aminomethyl-1H-pyrrole-2-carboxylicacid amides according to the invention of the general formula I arethose in which R² denotes a linear or branched, saturated orunsaturated, optionally at least mono-substituted aliphatic C₁₋₆residue, a saturated or unsaturated, optionally at least monosubstitutedcycloaliphatic C₃₋₈ residue optionally comprising at least oneheteroatom as a ring member and optionally attached via an optionally atleast mono-substituted C₁₋₃ alkylene group, an optionally at leastmono-substituted, five- or six-membered aryl or heteroaryl residue or anoptionally at least mono-substituted, five- or six-membered aryl orheteroaryl residue attached via an optionally substituted C₁₋₃ alkylenegroup, preferably a linear or branched, saturated aliphatic C₁₋₃residue, particularly preferably a methyl residue and the remainingresidues R¹ and R³ to R⁶ have the above-stated meaning, optionally inthe form of the pure stereoisomers thereof, in particular enantiomers ordiastereomers, the racemates thereof or in the form of mixtures of thestereoisomers, in particular the enantiomers, diastereomers or rotamers,in any desired mixing ratio, or in each case in the form of the acids orbases thereof or in the form of the salts thereof, in particular thephysiologically acceptable salts, or in each case in the form of thesolvates thereof, in particular the hydrates.

Further preferred substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acidamides according to the invention of the general formula I are those, inwhich the residues R¹ and R², together with the nitrogen atom joiningthem as a ring member, form a saturated or unsaturated, optionally atleast mono-substituted, five- or six-membered cycloaliphatic residue,which optionally comprises at least one further heteroatom selected fromthe group consisting of N, O and S as a ring member, preferably,together with the nitrogen atom joining them as a ring member, form asaturated, five- or six-membered cycloaliphatic residue optionallycomprising oxygen as a further ring member, particularly preferablytogether denote a (CH₂)₄, (CH₂)₅ or (CH₂)₂—O—(CH₂)₂ residue which, withthe nitrogen atom joining them as a ring member, forms a heterocycle,and in each case the remaining residues R³ to R⁶ have the above-statedmeaning, optionally in the form of the pure stereoisomers thereof, inparticular enantiomers or diastereomers, the racemates thereof or in theform of mixtures of the stereoisomers, in particular the enantiomers,diastereomers or rotamers, in any desired mixing ratio, or in each casein the form of the acids or bases thereof or in the form of the saltsthereof, in particular the physiologically acceptable salts, or in eachcase in the form of the solvates thereof, in particular the hydrates.

Further preferred substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acidamides according to the invention of the general formula I are those, inwhich R³ denotes an unsubstituted or at least mono-substituted, five- orsix-membered aryl or heteroaryl residue or an aryl ester, heteroarylester or alkyl ester group, preferably an optionally at leastmono-substituted phenyl residue or an alkyl ester group with C₁₋₃,preferably C₁₋₂, in the alkyl moiety, and in each case the residues R¹,R² and R⁴ to R⁶ have the above-stated meaning, optionally in the form ofthe pure stereoisomers thereof, in particular enantiomers ordiastereomers, the racemates thereof or in the form of mixtures of thestereoisomers, in particular the enantiomers, diastereomers or rotamers,in any desired mixing ratio, or in each case in the form of the acids orbases thereof or in the form of the salts thereof, in particular thephysiologically acceptable salts, or in each case in the form of thesolvates thereof, in particular the hydrates.

Further preferred substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acidamides according to the invention of the general formula I are those inwhich the residues R⁴ and R⁵, identical or different, denote hydrogen, alinear or branched, saturated or unsaturated, optionally at leastmono-substituted aliphatic C₁₋₆ residue, a saturated or unsaturated,optionally at least monosubstituted cycloaliphatic C₃₋₈ residueoptionally comprising at least one heteroatom as a ring member andoptionally attached via an optionally at least mono-substituted C₁₋₃alkylene group, an optionally at least mono-substituted, five- orsix-membered aryl or heteroaryl residue or an optionally at leastmono-substituted, five- or six-membered aryl or heteroaryl residueattached via an optionally substituted C₁₋₃ alkylene group, preferablyhydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, cyclopentyl,cyclohexyl, benzyl or phenethyl, and in each case the residues R¹ to R³and R⁶ have the above-stated meaning, optionally in the form of the purestereoisomers thereof, in particular enantiomers or diastereomers, theracemates thereof or in the form of mixtures of the stereoisomers, inparticular the enantiomers, diastereomers or rotamers, in any desiredmixing ratio, or in each case in the form of the acids or bases thereofor in the form of the salts thereof, in particular the physiologicallyacceptable salts, or in each case in the form of the solvates thereof,in particular the hydrates.

Likewise preferred substituted 5-aminomethyl-1H-pyrrole-2-carboxylicacid amides according to the invention of the general formula I arethose, in which the residues R⁴ and R⁵, together with the nitrogen atomjoining them as a ring member, form a saturated or unsaturated,optionally at least mono-substituted, five-, six- or seven-memberedcycloaliphatic residue, which optionally comprises at least one furtherheteroatom selected from the group consisting of N, O and S as a ringmember, preferably, together with the nitrogen atom joining them as aring member, form a saturated, five- or six-membered cycloaliphaticresidue optionally comprising oxygen as a further ring member,particularly preferably together denote a (CH₂)₄, (CH₂)₅ or(CH₂)₂—O—(CH₂)₂ residue which, with the nitrogen atom joining them as aring member, forms a heterocycle, and in each case the remainingresidues R¹ to R³ and R⁶ have the above-stated meaning, optionally inthe form of the pure stereoisomers thereof, in particular enantiomers ordiastereomers, the racemates thereof or in the form of mixtures of thestereoisomers, in particular the enantiomers, diastereomers or rotamers,in any desired mixing ratio, or in each case in the form of the acids orbases thereof or in the form of the salts thereof, in particular thephysiologically acceptable salts, or in each case in the form of thesolvates thereof, in particular the hydrates.

Further preferred substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acidamides according to the invention of the general formula I are those, inwhich R⁶ denotes a linear or branched, saturated or unsaturated,optionally at least mono-substituted aliphatic C₁₋₆ residue, a saturatedor unsaturated, optionally at least monosubstituted cycloaliphatic C₃₋₈residue optionally comprising at least one heteroatom as a ring memberand optionally attached via an optionally at least mono-substituted C₁₋₃alkylene group, an optionally at least mono-substituted, five- orsix-membered aryl or heteroaryl residue or an optionally at leastmono-substituted, five- or six-membered aryl or heteroaryl residueattached via an optionally at least mono-substituted C₁₋₃ alkylenegroup, preferably a linear or branched, saturated aliphatic C₁₋₃residue, particularly preferably a methyl residue and the residues R¹ toR⁵ in each case have the above-stated meaning, optionally in the form ofthe pure stereoisomers thereof, in particular enantiomers ordiastereomers, the racemates thereof or in the form of mixtures of thestereoisomers, in particular the enantiomers, diastereomers or rotamers,in any desired mixing ratio, or in each case in the form of the acids orbases thereof or in the form of the salts thereof, in particular thephysiologically acceptable salts, or in each case in the form of thesolvates thereof, in particular the hydrates.

If one of the above-stated residues R¹ to R⁶ denotes an aliphatic orcycloaliphatic residue which is mono- or polysubstituted, thesubstituents may preferably be selected from the group consisting ofhalogen, hydroxy, CN, CF₃, CHF₂, CH₂F, C₁₋₆ alkyl, C₁₋₆ alkoxy andoptionally at least mono-substituted phenyl, particularly preferablyfrom the group consisting of F, Cl, Br and hydroxy. If the phenylsubstituent is itself mono- or polysubstituted, the substituents thereofmay preferably be selected from the group consisting of hydroxy, CN,CF₃, CHF₂, CH₂F, C₁₋₆ alkyl and C₁₋₆ alkoxy.

If the above-stated residues R¹ to R⁶ comprise a mono- orpolysubstituted alkylene group, the substituents thereof may preferablybe selected from the group consisting of halogen, hydroxy, CN, CF₃,CHF₂, CH₂F, C₁₋₆ alkoxy and optionally at least mono-substituted phenyl,particularly preferably from the group consisting of F, Cl, Br andhydroxy. If the phenyl substituent is itself mono- or polysubstituted,the substituents thereof may preferably be selected from the groupconsisting of hydroxy, CN, CF₃, CHF₂, CH₂F, C₁₋₆ alkyl and C₁₋₆ alkoxy.

If one of the above-stated residues R¹ to R⁶ comprises a mono- orpolysubstituted aryl or heteroaryl residue, the correspondingsubstituents may preferably be selected from the group consisting ofhalogen, hydroxy, CN, CF₃, CHF₂, CH₂F, NO₂, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxyand optionally at least mono-substituted phenyl, particularly preferablyfrom the group consisting of F, Cl, Br, hydroxy, OCH₃ and CH₃. If thephenyl substituent is itself mono- or polysubstituted, the substituentsthereof may preferably be selected from the group consisting of hydroxy,CN, CF₃, CHF₂, CH₂F, C₁₋₆ alkyl and C₁₋₆ alkoxy.

If one of the above-stated residues R¹ to R⁶ denotes a cycloaliphaticresidue with at least one heteroatom or a heteroaryl residue, theheteroatoms, unless stated otherwise, may preferably be selected fromthe group consisting of oxygen, nitrogen and sulfur.

Suitable aliphatic residues, which are optionally mono- orpolysubstituted, may for example be selected from the group consistingof methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert.-butyl,n-pentyl, iso-pentyl, neopentyl, n-hexyl, 2-hexyl, n-heptyl, n-octyl,vinyl, ethynyl, propenyl, propynyl, butenyl, butynyl, pentenyl,pentynyl, hexenyl, hexynyl, heptyl, heptynyl, octenyl and octyl.

Suitable cycloaliphatic residues, which are optionally mono- orpolysubstituted and/or optionally comprise at least one heteroatom, mayfor example be selected from the group consisting of cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, pyrrolidinyl,piperidinyl, piperazinyl and morpholinyl.

Suitable alkylene groups, which are optionally mono- or polysubstituted,may for example be selected from the group consisting of methylene—(CH₂)—, ethylene —(CH₂)₂—, propylene —(CH₂)₃—, butylene —(CH₂)₄—,pentylene —(CH₂)₅— and hexylene —(CH₂)₆—, in each case optionally alsobranched.

Suitable aryl residues, which are optionally mono- or polysubstituted,are for example phenyl or naphthyl, preferably phenyl.

Suitable heteroaryl residues, which are optionally mono- orpolysubstituted, may for example be selected from the group consistingof pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, pyridinyl,pyridazinyl and pyrimidinyl.

Very particularly preferred substituted5-aminomethyl-1H-pyrrole-2-carboxylic acid amides according to theinvention are those selected from the group consisting of

-   5-[dimethylamino-(4-fluoro-phenyl)-methyl]-1H-methyl-1H-pyrrole-2-carboxylic    acid cyclohexylamide,-   5-[dimethylamino-(4-fluoro-phenyl)-methyl]-1-methyl-1H-pyrrole-2-carboxylic    acid butylamide,-   {5-[dimethylamino-(4-fluoro-phenyl)-methyl]-1-methyl-1H-pyrrol-2-yl}-pyrrolidin-1-yl-methanone,-   5-[dimethylamino-(4-bromo-phenyl)-methyl]-1-methyl-1H-pyrrole-2-carboxylic    acid cyclohexylamide,-   5-[dimethylamino-(4-bromo-phenyl)-methyl]-1-methyl-1H-pyrrole-2-carboxylic    acid butylamide,-   {5-[(4-bromo-phenyl)-dimethylamino-methyl]-1-methyl-1H-pyrrol-2-yl}-pyrrolidin-1-yl-methanone,-   5-[(4-bromo-phenyl)-dimethylamino-methyl]-1-methyl-1H-pyrrole-2-carboxylic    acid phenethyl-amide,-   {5-[(4-bromo-phenyl)-dimethylamino-methyl]-1-methyl-1H-pyrrol-2-yl}-morpholin-4-yl-methanone,-   5-(dimethylamino-phenyl-methyl)-1-methyl-1H-pyrrole-2-carboxylic    acid cyclohexylamide,-   5-(dimethylamino-phenyl-methyl)-1-methyl-1H-pyrrole-2-carboxylic    acid butylamide,-   [5-(dimethylamino-phenyl-methyl)-1-methyl-1H-pyrrol-2-yl]-pyrrolidin-1-yl-methanone,-   (5-butylcarbamoyl-1-methyl-1H-pyrrol-2-yl)-dimethylamino-acetic acid    ethyl ester,-   (5-cyclohexylcarbamoyl-1-methyl-1H-pyrrol-2-yl)-dimethylamino-acetic    acid ethyl ester,-   (5-butylcarbamoyl-1-methyl-1H-pyrrol-2-yl)-piperidin-1-yl-acetic    acid ethyl ester and-   (5-cyclohexylcarbamoyl-1-methyl-1H-pyrrol-2-yl)-piperidin-1-yl-acetic    acid ethyl ester,    optionally in the form of the pure stereoisomers thereof, in    particular enantiomers or diastereomers, the racemates thereof or in    the form of mixtures of the stereoisomers, in particular the    enantiomers, diastereomers or rotamers, in any desired mixing ratio,    or in each case in the form of the acids or bases thereof or in the    form of the salts thereof, in particular the physiologically    acceptable salts, particularly preferably the hydrochlorides, or in    each case in the form of the solvates thereof, in particular the    hydrates.

The present invention also provides a process for the production ofsubstituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amides accordingto the invention of the general formula I, in accordance with which asubstituted 1H-pyrrole-2-carboxylic acid amide of the general formula II

in which the residues R⁴, R⁵ and R⁶ have the above-stated meaning, arereacted using conventional methods known to the person skilled in theart, preferably in a suitable solvent, such as for example CH₂Cl₂,CH₃CN, dimethylformamide (DMF) or mixtures of at least two of thesesolvents, at room temperature (approx. 20-25° C.) with an iminium saltof the general formula III,

in which R¹ to R³ have the above-stated meaning and A⁻ denotes asuitable anion, preferably Cl⁻, AlCl₄ ⁻, Br⁻, I⁻ or CF₃—SO₃ ⁻ (triflateanion), to yield a substituted 5-aminomethyl-1H-pyrrole-2-carboxylicacid amide according to the invention of the general formula I and thislatter compound is optionally purified using conventional methods knownto the person skilled in the art, preferably by extraction, andoptionally isolated.

The compounds of the general formula II may be produced usingconventional methods known to the person skilled in the art, for examplefrom the commercially obtainable reagents of the general formula IV

in which R⁶ has the above-stated meaning, such as for example describedin A. J. Carpenter, D. J. Chadwick, Journal of Organic Chemistry, 1985,50, pages 4362-4368. The corresponding literature description is herebyintroduced as a reference and is deemed to be part of the disclosure.

The iminium salts of the general formula III may likewise be obtainedusing conventional methods known to the person skilled in the art, forexample from the corresponding aminals of the general formula V below

in which the residues R¹, R² and R³ have the above-stated meaning, asfor example described in D. Seebach et al., Helv. Chim. Acta 1988, 71,pages 1999-2001 and N. Risch et al., Synthesis 1998, 11, pages1609-1614. The corresponding literature descriptions are herebyintroduced as a reference and are deemed to be part of the disclosure.

The aminals of the general formula V may also be produced in accordancewith methods known from the literature, as for example described in D.Seebach et al., Helv. Chim. Acta 1988, 71, pages 1999-2001 and N. Rischet al., Synthesis 1998, 11, pages 1609-1614. The correspondingliterature descriptions are hereby introduced as a reference and aredeemed to be part of the disclosure.

The substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amidesaccording to the invention of the general formula I and correspondingstereoisomers may be isolated not only in the form of the free bases orfree acids thereof, but also in the form of corresponding salts.

The free bases of the respective 5-aminomethyl-1H-pyrrole-2-carboxylicacid amides according to the invention of the general formula I andcorresponding stereoisomers may, for example, be converted into thecorresponding physiologically acceptable salts by reaction with aninorganic or organic acid, preferably with hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid,p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid, oxalicacid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lacticacid, citric acid, glutamic acid or aspartic acid.

The free bases of the respective 5-aminomethyl-1H-pyrrole-2-carboxylicacid amides according to the invention of the general formula I andcorresponding stereoisomers may preferably be converted into thecorresponding hydrochlorides by combining the compounds of the generalformula I or corresponding stereoisomers as free bases dissolved in asuitable organic solvent, such as for example butan-2-one (methyl ethylketone), with trimethylsilyl chloride (TMSCI).

The free bases of the respective 5-aminomethyl-1H-pyrrole-2-carboxylicacid amides of the general formula I and corresponding stereoisomers maylikewise be converted into the corresponding physiologically acceptablesalts with the free acid or a salt of a sugar substitute, such as forexample saccharin, cyclamate or acesulfame.

The free acids of the respective 5-aminomethyl-1H-pyrrole-2-carboxylicacid amides of the general formula I and corresponding stereoisomers mayaccordingly be converted into the corresponding physiologicallyacceptable salts by reaction with a suitable base.

The 5-aminomethyl-1H-pyrrole-2-carboxylic acid amides according to theinvention of the general formula I and corresponding stereoisomers mayoptionally, like the corresponding acids, the corresponding bases orsalts of these compounds, also be obtained in the form of the solvatesthereof, preferably the hydrates thereof.

If the substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amidesaccording to the invention of the general formula I are obtained afterthe production thereof in the form of the stereoisomers thereof,preferably in the form of the racemates thereof or other mixtures oftheir various enantiomers and/or diastereomers, these may be separatedand optionally isolated by conventional methods known to the personskilled in the art. Examples which may be mentioned are chromatographicseparation processes, in particular liquid chromatography processes atstandard pressure or at elevated pressure, preferably MPLC and HPLCprocesses, and fractional crystallisation processes. Individualenantiomers, e.g. diastereomeric salts formed by means of HPLC on achiral phase or by means of crystallisation with chiral acids, such as(+)-tartaric acid, (−)-tartaric acid or (+)-10-camphorsulfonic acid, mayhere in particular be separated from one another.

The substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amidesaccording to the invention of the general formula I and correspondingstereoisomers as well as in each case the corresponding acids, bases,salts and solvates are toxicologically safe and are therefore suitableas pharmaceutical active ingredients in pharmaceutical preparations.

The present invention accordingly further provides pharmaceuticalpreparations containing at least one substituted5-aminomethyl-1H-pyrrole-2-carboxylic acid amide according to theinvention of the general formula I, optionally in the form of theracemate thereof, the pure stereoisomers thereof, in particularenantiomers or diastereomers, or in the form of mixtures of thestereoisomers, in particular the enantiomers, diastereomers or rotamers,in any desired mixing ratio, or in each case in the form of the acids orthe bases thereof or in the form of the salts thereof, in particular thephysiologically acceptable salts, particularly preferably thehydrochlorides, or in each case in the form of the solvates thereof, inparticular the hydrates, and optionally physiologically acceptableauxiliary substances.

These pharmaceutical preparations are in particular suitable forregulating the ORL (“opioid receptor like”)-1 receptor, for regulatingthe μ opioid receptor, for inhibiting noradrenalin uptake and forinhibiting 5-hydroxytryptamine (5-HT) uptake.

The pharmaceutical preparations according to the invention are likewisepreferably suitable for combatting pain, preferably for combattingchronic pain and/or acute pain and/or neuropathic pain.

The pharmaceutical preparations according to the invention arefurthermore also suitable for the treatment of withdrawal symptoms,memory disorders, neurodegenerative diseases, preferably Parkinson'sdisease, Huntington's chorea or Alzheimer's disease, epilepsy, disordersof the cardiovascular system, water retention conditions, intestinalmotility (diarrhoea), urinary incontinence, anorexia, pruritus,depression, tinnitus, sexual dysfunction, preferably erectiledysfunction, respiratory diseases, or for diuresis, for influencing thecardiovascular system, preferably for vasodilating the arteries, forsuppression of the urinary reflex, for anxiolysis, for regulating theelectrolyte balance, for regulating, preferably stimulating, foodintake, for reducing the addictive potential of opioids, in particularof morphine, for modulating locomotor activity, for influencing theaction of μ agonists, in particular morphine.

The present invention also provides the use of one or more substituted5-aminomethyl-1H-pyrrole-2-carboxylic acid amides of the general formulaI, optionally in the form of the pure stereoisomers thereof, inparticular enantiomers or diastereomers, the racemates thereof or in theform of mixtures of the stereoisomers, in particular the enantiomers,diastereomers or rotamers, in any desired mixing ratio, or in each casein the form of the acids or bases thereof or in the form of the saltsthereof, in particular the physiologically acceptable salts,particularly preferably the hydrochlorides, or in each case in the formof the solvates thereof, in particular the hydrates, for the productionof a pharmaceutical preparation for regulating the ORL (“opioid receptorlike”)-1 receptor, for regulating the μ opioid receptor, for inhibitingnoradrenalin uptake or for inhibiting 5-hydroxytryptamine (5-HT) uptake.

The present invention also provides the use of one or more substituted5-aminomethyl-1H-pyrrole-2-carboxylic acid amides of the general formulaI, optionally in the form of the pure stereoisomers thereof, inparticular enantiomers or diastereomers, the racemates thereof or in theform of mixtures of the stereoisomers, in particular the enantiomers,diastereomers or rotamers, in any desired mixing ratio, or in each casein the form of the acids or bases thereof or in the form of the saltsthereof, in particular the physiologically acceptable salts,particularly preferably the hydrochlorides, or in each case in the formof the solvates thereof, in particular the hydrates, for the productionof a pharmaceutical preparation for combatting pain, preferably chronicpain and/or acute pain and/or neuropathic pain, for the treatment ofwithdrawal symptoms, memory disorders, neurodegenerative diseases,preferably Parkinson's disease, Huntington's chorea or Alzheimer'sdisease, epilepsy, disorders of the cardiovascular system, waterretention conditions, intestinal motility (diarrhoea), urinaryincontinence, anorexia, pruritus, depression, tinnitus, sexualdysfunction, preferably erectile dysfunction, respiratory diseases, orfor diuresis, for the suppression of the urinary reflex, for anxiolysis,for regulating the electrolyte balance, for influencing thecardiovascular system, preferably for vasodilating the arteries, forregulating, preferably stimulating, food intake, for reducing theaddictive potential of opioids, in particular of morphine, formodulating locomotor activity or for influencing the action of μagonists, in particular morphine.

The pharmaceutical preparations according to the invention may bepresent as liquid, semisolid or solid dosage forms, for example in theform of solutions for injection, drops, succi, syrups, sprays,suspensions, tablets, patches, capsules, transdermal delivery systems,suppositories, ointments, creams, lotions, gels, emulsions, aerosols orin multiparticulate form, for example in the form of pellets orgranules, optionally press-moulded into tablets, packaged in capsules orsuspended in a liquid, and also be administered as such.

Apart from one or more substituted 5-aminomethyl-1H-pyrrole-2-carboxylicacid amides of the general formula I, optionally in the form of theracemates thereof, the pure stereoisomers thereof, in particularenantiomers or diastereomers, or in the form of mixtures of thestereoisomers, in particular the enantiomers or diastereomers, in anydesired mixing ratio, or in each case in the form of the acid thereof orthe base thereof or in the form of the salt thereof, in particular aphysiologically acceptable salt, or in the form of the solvate thereof,in particular the hydrate, the pharmaceutical preparations according tothe invention conventionally contain further physiologically acceptablepharmaceutical auxiliary substances, which are preferably selected fromthe group consisting of matrix materials, fillers, solvents, diluents,surface-active substances, dyes, preservatives, disintegrants, slipagents, lubricants, aromas and binders.

Selection of the physiologically acceptable auxiliary substances and thequantities thereof which are to be used depends upon whether thepharmaceutical preparation is to be administered orally, subcutaneously,parenterally, intravenously, intraperitoneally, intradermally,intramuscularly, intranasally, buccally, rectally or topically, forexample onto infections of the skin, mucous membranes or eyes.

Preparations in the form of tablets, coated tablets, capsules, granules,pellets, drops, succi and syrups are preferred for oral administration,while solutions, suspensions, readily reconstitutible dried preparationsand sprays are preferred for parenteral, topical and inhalatoryadministration.

Substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amides of thegeneral formula I, optionally in the form of the racemates thereof, thepure stereoisomers thereof, in particular enantiomers or diastereomers,or in the form of mixtures of the stereoisomers, in particular theenantiomers or diastereomers, in any desired mixing ratio, or in eachcase in the form of the acid thereof or the base thereof or in the formof the salt thereof, in particular a physiologically acceptable salt, orin the form of the solvate thereof, in particular the hydrate, in adepot in dissolved form or in a dressing, optionally with the additionof skin penetration promoters, are suitable percutaneous administrationpreparations.

Orally or percutaneously administrable formulations may also release theparticular substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amidesof the general formula I, optionally in the form of the racematesthereof, the pure stereoisomers thereof, in particular enantiomers ordiastereomers, or in the form of mixtures of the stereoisomers, inparticular the enantiomers or diastereomers, in any desired mixingratio, or in each case in the form of the acid thereof or the basethereof or in the form of the salt thereof, in particular aphysiologically acceptable salt, or in the form of the solvate thereof,in particular the hydrate, in delayed manner. Production of thepharmaceutical preparations according to the invention proceeds with theassistance of conventional means, devices, methods and processes knownto the person skilled in the art, such as are described for example inA. R. Gennaro (ed.), “Remington's Pharmaceutical Sciences”, 17thedition, Mack Publishing Company, Easton, Pa. (1985), in particular inpart 8, chapters 76 to 93. The corresponding literature description ishereby introduced as a reference and is deemed to be part of thedisclosure.

The quantity of the particular substituted5-aminomethyl-1H-pyrrole-2-carboxylic acid amide of the general formulaI to be administered to patients, optionally in the form of theracemate, the pure stereoisomers, in particular enantiomers ordiastereomers, or in the form of mixtures of the stereoisomers, inparticular the enantiomers or diastereomers, in any desired mixingratio, or in each case in the form of the acid or base or in the form ofthe salt, in particular a physiologically acceptable salt, or in eachcase in the form of the solvate, in particular the hydrate, may vary andis for example dependent on the weight or age of the patient and on themode of administration, the indication and the severity of thecomplaint. Conventionally, 0.005 to 500 mg/kg, preferably 0.05 to 5mg/kg of patient body weight of at least one substituted5-aminomethyl-1H-pyrrole-2-carboxylic acid amide of the general formulaI, optionally in the form of the racemate thereof, the purestereoisomers thereof, in particular enantiomers or diastereomers, or inthe form of mixtures of the stereoisomers, in particular the enantiomersor diastereomers, in any desired mixing ratio, or in each case in theform of the acid thereof or the base thereof or in the form of the saltthereof, in particular a physiologically acceptable salt, or in the formof the solvate thereof, in particular the hydrate, are administered.

For simplicity and illustrative purposes, the principles of the presentinvention are described by referring to various examples. One ofordinary skill in the art will readily recognize that the sameprinciples are equally applicable to, and can be implemented in otherforms, and that any such variation would be within those modificationsthat do not part from the true spirit and scope of the presentinvention. The invention is not limited in its application to thedetails of any particular formulation shown, since the invention iscapable of other embodiments. The following examples are provided forillustrative purposes and do not and should not be understood to limitthe claims appended hereto. The terminology used herein is for thepurpose of description and not of limitation.

Pharmacological Methods:

a) Method for Determining Affinity for the ORL-1 Receptor

The affinity of the particular substituted5-aminomethyl-1H-pyrrole-2-carboxylic acid amide of the general formulaI for the ORL-1 receptor was determined in a receptor binding assay with³H-nociceptin/Orphanin FQ with membranes of recombinant CHO—ORL1 cells,as described by Ardati et al. in Mol. Pharmacol., 51, 1997, pages816-824. The corresponding literature description is hereby introducedas a reference and is deemed to be part of the disclosure.

The concentration of ³H-nociceptin/Orphanin FQ in these tests was 0.5nM. The binding assays were in each case performed with 20 μg ofmembrane protein per 200 μl batch in 50 mM Hepes, pH 7.4, 10 mM MgCl₂and 1 mM EDTA. Binding to the ORL1 receptor was determining using 1 mgportions of WGA-SPA Beads (Amersham-Pharmacia, Freiburg, Germany), byone hour's incubation of the batch at room temperature (approx. 20-25°C.) and subsequent measurement in a Trilux scintillation counter(Wallac, Finland).

b) Method for Determining Affinity for the Human μ Opiate Receptor

Receptor affinity for the human μ opiate receptor was determined in ahomogeneous batch in microtitre plates. To this end, dilution series ofthe particular substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acidamide of the general formula I to be tested were incubated at roomtemperature for 90 minutes in a total volume of 250 μl with a receptormembrane preparation (15-40 μg of protein per 250 μl of incubationbatch) of CHO—K1 cells, which express the human μ opiate receptor(RB—HOM receptor membrane preparation from NEN, Zaventem, Belgium) inthe presence of 1 nmol/l of the radioactive ligand [³H]-naloxone(NET719, from NEN, Zaventem, Belgium) and of 1 mg of WGA-SPA beads(wheat germ agglutinin SPA beads from Amersham/Pharmacia, Freiburg,Germany). The incubation buffer used was 50 mmol/l tris-HCl supplementedwith 0.05 wt. % of sodium azide and with 0.06 wt. % of bovine serumalbumin. 25 μmol/l of naloxone were additionally added to determinenonspecific binding. Once the ninety minute incubation time had elapsed,the microtitre plates were centrifuged off for 20 minutes at 1000 g andthe radioactivity measured in a β-Counter (Microbeta-Trilux, fromPerkinElmer Wallac, Freiburg, Germany). The percentage displacement ofthe radioactive ligand from its binding to the human μ opiate receptorwas determined at a concentration of the compounds to be tested of 1μmol/l and stated as percentage inhibition of specific binding. On thebasis of the percentage displacement by different concentrations of thecompounds to be tested of the general formula I, IC₅₀ inhibitionconcentrations which bring about 50% displacement of the radioactiveligand were calculated. K_(i) values for the test substances wereobtained by conversion using the Cheng-Prusoff equation.

c) Method for Determining Noradrenalin and the 5-HT Uptake Inhibition:

Synaptosomes from rat brain regions (the “P2” fraction was used) werefreshly isolated for in vitro studies, as described in the publication“The isolation of nerve endings from brain” by E. G. Gray and V. P.Whittaker, J. Anatomy 76, pages 79-88, 1962. The correspondingliterature description is hereby introduced as a reference and is deemedto be part of the disclosure.

The tissue (hypothalamus for the determination of noradrenalin uptakeinhibition and medulla and pons for the determination of 5-HT uptakeinhibition) was homogenised in ice-cooled 0.32 M sucrose (100 mg oftissue/1 mL) in a glass homogeniser with teflon pestle using fivecomplete up and down strokes at 840 revolutions/minute.

The homogenate was centrifuged at 4° C. for 10 minutes at 1000 g. Aftersubsequent centrifugation at 17000 g for 55 minutes, the synaptosomes(P₂ fraction) were obtained, which were resuspended in 0.32 M glucose(0.5 mL/100 mg of original weight).

The particular uptake was measured in a 96-well microtitre plate. Thevolume was 250 μl and the incubation proceeded at room temperature(approx. 20-25° C.) under an O₂ atmosphere.

The incubation time was 7.5 minutes for [³H]-NA and 5 minutes for[³H]-5-HT. The 96 samples were then filtered through a Unifilter GF/B®microtitre plate (Packard) and washed with 200 ml of incubated bufferusing a “Brabdel MPXRI-96T Cell-Harvester”. The Unifilter GF/B plate wasdried for 1 hour at 55° C. The plate was then sealed with a Back seal®(Packard) and 35 μl of scintillation fluid were added per well (Ultimagold®, Packard). After sealing with a top seal® (Packard) andestablishment of equilibrium (around 5 hours), radioactivity wasdetermined in a “Trilux 1450 Microbeta” (Wallac).

The following characteristics were determined for the NA transporter:

-   NAuptake: Km=0.32±0.11 μM

The quantity of protein used in the above determination corresponded tothe values known from the literature, as for example described in“Protein measurement with the folin phenol reagent”, Lowry et al., J.Biol. Chem., 193, 265-275, 1951. A detailed description of the methodmay also be found in the literature, for example in M.Ch. Frink, H.-H.Hennies, W. Engelberger, M. Haurand and B. Wilffert (1996)Arzneim.-Forsch./Drug Res. 46 (III), 11, 1029-1036. The correspondingliterature descriptions are hereby introduced as a reference and aredeemed to be part of the disclosure.

d) Investigation of Analgesic Efficacy by the Writhing Test

Investigation of the compounds according to the invention of the generalformula I for analgesic efficacy was performed by phenylquinone-inducedwrithing in the mouse, modified after I. C. Hendershot and J. Forsaith(1959) J. Pharmacol. Exp. There. 125. 237-240. The correspondingliterature description is hereby introduced as a reference and is deemedto be part of the disclosure.

Male NMRI mice weighing from 25 to 30 g were used for this purpose.Groups of 10 animals per substance dose received, 10 minutes afterintravenous administration of the compounds to be tested, 0.3 ml/mouseof a 0.02% aqueous solution of phenylquinone (phenylbenzoquinone, Sigma,Deisenhofen, Germany; solution prepared with addition of 5% of ethanoland stored in a water bath at 45° C.) administered intraperitoneally.The animals were placed individually in observation cages. A push buttoncounter was used to record the number of pain-induced stretchingmovements (writhing reactions=straightening of the torso with stretchingof the rear extremities) for 5-20 minutes after phenylquinoneadministration. The control was provided by animals which had receivedonly physiological common salt solution. All the compounds were testedat the standard dosage of 10 mg/kg.

The invention is explained below with reference to Examples. Theseexplanations are given merely by way of example and do not restrict thegeneral concept of the invention.

EXAMPLES

The NMR spectra were measured on a Bruker DPX 300 instrument for the 300MHz spectra and on a Bruker DRX 600 instrument for the 600 MHz spectra.

The particular chemicals and solvents were purchased from theconventional manufacturers.

A) General Synthesis Method for the Production of Compounds of theGeneral Formula II:

The particular pyrrole-2-carboxylic acid (50 mmol) of the generalformula IV was suspended in 200 ml of toluene. Then, with cooling in anice bath, 100 mmol of sodium hydride (NaH) were slowly added and themixture stirred for approx. 10 minutes at room temperature.

After addition of 200 mmol of oxalyl chloride, the reaction mixture wasrefluxed for 15 minutes and then the excess oxalyl chloride and thesolvent were removed in a rotary evaporator.

The resultant residue was redissolved in 200 ml of diethyl ether, slowlycombined with 100 mmol of the corresponding amine and the resultantreaction mixture was refluxed for two hours. After cooling, the reactionmixture was washed three times with 50 ml portions of water. The organicphase was separated, dried with magnesium sulfate and evaporated in arotary evaporator. The resultant crude product was used without furtherpurification in the following synthesis steps.

The compounds of the general formula II produced by the above generalsynthesis method are listed in Table 1 below: TABLE 1 Compound R⁴ R⁵ R⁶II-1 —(CH₂)₂—O—(CH₂)₂— CH₃ II-2 N-methylpiperazinyl CH₃ II-3N-phenylpiperazinyl CH₃ II-4 —(CH₂)₅— CH₃ II-5 —(CH₂)₄— CH₃ II-6(CH₂)₂phenyl H CH₃ II-7 CH₂phenyl CH₃ CH₃ II-8 CH₂phenyl CH(CH₃)₂ CH₃II-9 CH₂phenyl CH₂phenyl CH₃ II-10 CH₂-2-pyridine H CH₃ II-11CH₂-3-pyridine H CH₃ II-12 CH₂-4-fluorophenyl H CH₃ II-13 CH₂-2-furyl HCH₃ II-14 CH₂-2-methoxyphenyl H CH₃ II-15 (CH₂)₂-4-methoxyphenyl H CH₃II-16 (CH₂)₂-3,4- H CH₃ dimethoxyphenyl II-17 cyclopropyl H CH₃ II-18cyclohexyl H CH₃ II-19 cyclohexyl CH₃ CH₃ II-20 cyclohexyl cyclohexylCH₃ II-21 cyclooctyl H CH₃ II-22 (CH₂)₃CH₃ H CH₃ II-23 (CH₂)₃CH₃ CH₃ CH₃II-24 (CH₂)₂-morpholino H CH₃ II-25 (CH₂)₃-morpholino H CH₃

The structure of the compounds II-1 to II-25 was in each case determinedby means of ¹H-NMR spectroscopy. The chemical shifts of selectedcompounds are shown below.

(1-Methyl-1H-pyrrol-2-yl)-morpholin-4-yl-methanone

δ (DMSO, 300 MHz)=3.58-3.66 (m, 8H, N(CH₂CH₂)₂O, N(CH₂CH₂)₂O); 3.69 (s,3H, NCH₃); 5.98-6.05 (m, 1H, N(CH₃)]—CHCHCHC—[); 6.24-6.32 (m, 1H,N(CH₃)]—CHCHCHC—[); 6.78-6.88 (m, 1H, N(CH₃)]—CHCHCHC—[).

II-2)

(4-Methylpiperazin-1-yl)-(1-methyl-1H-pyrrol-2-yl)-methanone

δ (DMSO, 300 MHz)=2.21 (s, 3H, N—CH₃); 2.28-2.39 (m, 4H, N(CH₂CH₂)₂NMe);3.57-3.64 (m, 4H, N(CH₂CH₂)₂NMe); 3.66 (s, 3H, NCH₃); 6.01 (dd, 1H,J=3.7 Hz, J=1.5 Hz, N(CH₃)]—CHCHCHC—[); 6.26 (dd, 1H, J=1.5 Hz, J=4.5Hz, N(CH₃)]—CHCHCHC—[); 6.82-6.85 (m, 1H, N(CH₃)—]—CHCHCHC—[).

II-3)

(1-Methyl-1H-pyrrol-2-yl)-(4-phenyl-piperazin-1-yl)-methanone

δ (DMSO, 300 MHz)=3.13-3.23 (m, 4H, N(CH₂CH₂)₂NPh); 3.70 (s, 3H, NCH₃);3.73-3.83 (m, 4H, N(CH₂CH₂)₂NPh); 6.04 (dd, 1H, J=2.6 Hz, J=3.7 Hz,N(CH₃)]—CHCHCHC—[); 6.34 (dd, 1H, J=1.5 Hz, J=3.7 Hz,N(CH₃)]—CHCHCHC—[); 6.77-6.89 (m, 2H, N(CH₃)]—CHCHCHC—[, Ph); 6.91-6.99(m, 2H, Ph); 7.17-7.28 (m, 2H, Ph).

II-4)

(1-Methyl-1H-pyrrol-2-yl)-piperidin-1-yl-methanone

δ (DMSO, 300 MHz)=1.45-1.68 (m, 6H, N—[(CH₂)₂—CH₂—(CH₂)₂—[); 3.51-3.62(m, 4H, N—[(CH₂)₂—CH₂—(CH₂M); 3.65 (s, 3H, NCH₃); 5.97-6.03 (m, 1H,N(CH₃)—]—CHCHCHC—[); 6.21-6.25 (m, 1H, N(CH₃)]—CHCHCHC—[); 6.79-6.84 (m,1H, N(CH₃)]—CHCHCHC—[).

II-6)

1-Methyl-1H-pyrrole-2-carboxylic acid phenethylamide

δ (DMSO, 300 MHz)=2.73-2.88 (m, 2H, CH₂CH₂Ph); 3.34-3.48 (m, 2H,CH₂CH₂Ph); 3.84 (s, 3H, NCH₃); 5.92-6.01 (m, 1H, N(CH₃)]—CHCHCHC—[);6.65-6.75 (m, 1H, N(CH₃)—]—CHCHCHC—[); 6.75-6.84 (m, 1H,N(CH₃)—]—CHCHCHC—[);

7.10-7.36 (m, 5H, Ph); 7.95-8.08 (m, 1H, NH).

II-7)

1-Methyl-1H-pyrrole-2-carboxylic acid benzylmethylamide

δ (DMSO, 300 MHz)=2.99 (br. s, 3H, NCH₃Bn); 3.71 (s, 3H, NCH₃);4.65-4.75 (m, 2H, CH₂Ph); 5.96-6.04 (m, 1H, N(CH₃)]—CHCHCHC—[);6.28-6.41 (m, 1H, N(CH₃)—]—CHCHCHC—[); 6.87-6.93 (m, 1H,N(CH₃)—]—CHCHCHC—[); 7.18-7.43 (m, 5H, Ph).

II-8)

1-Methyl-1H-pyrrole-2-carboxylic acid benzylisopropylamide

δ (DMSO, 300 MHz)=1.15 (d, 3H, J=6.8 Hz, CH(CH₃)₂); 3.67 (s, 3H, NCH₃);4.52-4.67 (m, 3H, CH₂Ph, CH(CH₃)₂); 5.95-6.03 (m, 1H,N(CH₃)]—CHCHCHC—[); 6.25-6.34 (m, 1H, N(CH₃)—]—CHCHCHC—[); 6.80-6.86 (m,1H, N(CH₃)—]—CHCHCHC—[);

7.15-7.36 (m, 5H, Ph).

II-9)

1-Methyl-1H-pyrrole-2-carboxylic acid dibenzylamide

δ (DMSO, 300 MHz)=3.73 (s, 3H, NCH₃); 4.58-4.72 (m, 4H, CH₂Ph); 5.95(dd, 1H, J=2.6 Hz, J=6.0 Hz, N(CH₃)]—CHCHCHC—[); 6.23-6.29 (m, 1H,N(CH₃)—)—CHCHCHC—[); 6.88-6.93 (m, 1H, N(CH₃)—]—CHCHCHC—[); 7.16-7.42(m, 10H, Ph).

II-10)

1-Methyl-1H-pyrrole-2-carboxylic acid (pyridin-2-ylmethyl)-amide

δ (DMSO, 300 MHz)=3.85 (s, 3H, NCH₃); 4.49 (d, 2H, J=6.0 Hz,CH₂pyridine); 5.99-6.04 (m, 1H, N(CH₃)]—CHCHCHC—[); 6.83-6.89 (m, 2H,N(CH₃)—]CHCHCHC—[); 7.18-7.25 (m, 1H, pyridine); 7.30 (d, 1H, J=7.9 Hz,pyridine); 7.72 (dt, 1H, J=1.9 Hz, J=7.5 Hz, pyridine); 8.46-8.52 (m,1H, pyridine); 8.52-8.59 (m, 1H, NH).

II-11)

1-Methyl-1H-pyrrole-2-carboxylic acid (pyridin-3-ylmethyl)-amide

δ (DMSO, 300 MHz)=3.85 (s, 3H, NCH₃); 4.42 (d, 2H, J=6.0 Hz,CH₂pyridine); 5.98-6.02 (m, 1H, N(CH₃)]—CHCHCHC—[); 6.80-6.85 (m, 1H,N(CH₃)—]—CHCHCHC—[); 6.85-6.88 (m, 1H, N(CH₃)—]—CHCHCHC—[); 7.32 (dd,1H, J=4.9 Hz, J=7.5 Hz, pyridine); 7.65-7.71 (m, 1H, pyridine);8.42-8.45 (m, 1H, pyridine); 8.51-8.58 (m, 2H, pyridine, NH).

II-12)

1-Methyl-1H-pyrrole-2-carboxylic acid 4-fluoro-benzylamide

δ (DMSO, 300 MHz)=3.84 (s, 3H, NCH₃); 4.37 (d, 2H, J=6.0 Hz, CH₂₄-FPh);5.98-6.03 (m, 2H, N(CH₃)]—CHCHCHC—[); 6.88-6.90 (m, 1H,N(CH₃)]—CHCHCHC—[); 7.09-7.17 (m, 2H, 4-FPh); 7.28-7.36 (m, 2H, 4-FPh);8.47-8.58 (m, 1H, NH).

II-13)

1-Methyl-1H-pyrrole-2-carboxylic acid (furan-2-ylmethyl)-amide

δ (DMSO, 300 MHz)=3.85 (s, 3H, NCH₃); 4.38 (d, 2H, J=5.7 Hz, CONHCH₂);5.95-6.03 (m, 1H, O]—CHCHCHC—[); 6.19-6.26 (m, 1H, N(CH₃)]—CHCHCHC—[);6.34-6.40 (m, 1H, O]—CHCHCHC—[); 6.78-6.84 (m, 1H, N(CH₃)]—CHCHCHC—[);6.85-6.90 (m, 1H, N(CH₃)]—CHCHCHC—[); 7.49-7.56 (m, 1H, O]—CHCHCHC—[);8.36-8.46 (m, 1H, NH).

II-14)

1-Methyl-1H-pyrrole-2-carboxylic acid 2-methoxy-benzylamide

δ (DMSO, 300 MHz)=3.83 (s, 3H, NCH₃); 3.85 (s, 3H, OCH₃); 4.38 (d, 2H,J=6.0 Hz, CH₂-o-OMePh); 5.96-6.03 (m, 1H, N(CH₃)]—CHCHCHC—[); 6.81-7.00(m, 4H, N(CH₃)]—CHCHCHC—[, p-OMePh); 7.13-7.27 (m, 2H, p-OMePh);8.22-8.32 (m, 1H, NH).

II-15)

1-Methyl-1H-pyrrole-2-carboxylic acid [2-(4-methoxyphenyl)-ethyl]-amide

δ (DMSO, 300 MHz)=2.72 (d, 1H, J=7.1 Hz, CH₂CH₂-p-OMePh); 2.75 (d, 1H,J=7.9 Hz, CH₂CH₂-p-OMePh); 3.27-3.41 (m, 2H, CH₂CH₂-p-OMePh); 3.72 (s,3H, NCH₃); 3.83 (s, 3H, OCH₃); 5.93-6.01 (m, 1H, N(CH₃)]—CHCHCHC—[);6.66-6.73 (m, 1H, N(CH₃)—]—CHCHCHC—[); 6.78-6.88 (m, 3H,N(CH₃)]—CHCHCHC—[, p-OMePh); 7.13 (d, 2H, J=8.7 Hz, -[, p-OMePh);7.95-8.02 (m, 1H, NH).

II-16)

1-Methyl-1H-pyrrole-2-carboxylic acid[2-(3,4-dimethoxyphenyl)-ethyl]-amide

δ (DMSO, 300 MHz)=2.73 (d, 1H, J=7.5 Hz, CH₂CH₂(3.4-(OMe)₂Ph); 2.75 (d,1H, J=7.5 Hz, CH₂CH₂(3.4-(OMe)₂Ph); 3.34-3.45 (m, 2H,CH₂CH₂(3.4-(OMe)₂Ph);

3.73 (s, 3H, NCH₃); 5.97 (dd, 1H, J=2.6 Hz, J=3.0 Hz N(CH₃)]—CHCHCHC—[);6.70-6.75 (m, 2H, N(CH₃)]—CHCHCHC—[); 6.80-6.85 (m, 3H, (3.4-(OMe)₂Ph);7.91-8.01 (m, 1H, NH).

II-17)

1-Methyl-1H-pyrrole-2-carboxylic acid cyclopropylamide

δ (DMSO, 300 MHz)=0.47-0.68 (m, 4H,]—CH₂CHCH₂—[); 2.68-2.78 (m,1H,]—CH₂CHCH₂—[); 3.84 (s, 3H, NCH₃); 5.91-5.99 (m, 1H,N(CH₃)—]—CHCHCHC—[); 6.68-6.75 (m, 1H, N(CH₃)]—CHCHCHC—[); 6.77-6.84 (m,1H, N(CH₃)]—CHCHCHC—[); 7.89 (br. s, 1H, NH).

II-18)

1-Methyl-1H-pyrrole-2-carboxylic acid cyclohexylamide

1.02-1.39 (m, 6H, NH]—CH(CH₂)₂(CH₂)₂CH₂—[); 1.54-1.88 (m, 4H,NH]—CH(CH₂)₂(CH₂)₂CH₂—[); 3.60-3.78 (m, 1H, NH]—CH(CH₂)₂(CH₂)₂CH₂—[);3.83 (s, 3H, NCH₃); 5.92-6.00 (m, 1H, N(CH₃)]—CHCHCHC—[); 6.69-6.87 (m,2H, N(CH₃)]—CHCHCHC—[); 7.51-7.66 (m, 1H, NH).

II-19)

1-Methyl-1H-pyrrole-2-carboxylic acid cyclohexylmethylamide

δ (DMSO, 300 MHz)=0.88-1.36 (m, 4H, N]—CH(CH₂)₂(CH₂)₂CH₂—[); 1.44-1.85(m, 6H, N]—CH(CH₂)₂(CH₂)₂CH₂—[); 2.88 (s, 3H, N—CH₃); 3.64 (s, 3H,NCH₃); 4.03-4.19 (m, 1H, N]—CH(CH₂)₂(CH₂)₂CH₂—[); 5.97-6.04 (m, 1H,N(CH₃)]—CHCHCHC—[); 6.19-6.29 (m, 1H, N(CH₃)]—CHCHCHC—[); 6.79-6.85 (m,1H, N(CH₃)]—CHCHCHC—[).

II-20)

1-Methyl-1H-pyrrole-2-carboxylic acid dicyclohexylamide

δ (DMSO, 300 MHz)=1.03-1.33 (m, 6H, N]—CH(CH₂)₂(CH₂)₂CH₂—[); 1.49-1.83(m, 11 H, N]—CH(CH₂)₂(CH₂)₂CH₂—[); 1.84-2.14 (m, 3H,N]—CH(CH₂)₂(CH₂)₂CH₂—[); 3.38-3.55 (m, 2H, N]—CH(CH₂)₂(CH₂)₂CH₂—[); 3.64(s, 3H, NCH₃); 5.93-6.00 (m, 1H, N(CH₃)]—CHCHCHC—[); 6.03-6.11 (m, 1H,N(CH₃)]—CHCHCHC—[); 6.73-6.80 (m, 1H, N(CH₃)]—CHCHCHC—[).

II-21)

1-Methyl-1H-pyrrole-2-carboxylic acid cyclooctylamide

δ (DMSO, 300 MHz)=1.38-1.77 (m, 16H, NCH(CH₂)₇); 3.82 (s, 3H, NCH₃);3.88-4.02 (m, 1H, NCH(CH₂)₇); 5.93-5.99 (m, 1H, N(CH₃)]—CHCHCHC—[);6.75-6.83 (m, 2H, N(CH₃)—]—CHCHCHC—[); 7.68-7.59 (m, 1H, NH).

II-22)

1-Methyl-1H-pyrrole-2-carboxylic acid butylamide

δ (DMSO, 300 MHz)=0.90 (t, 3H, J=7.2 Hz, CH₃CH₂CH₂CH₂); 1.21-1.40 (m,2H, CH₃CH₂CH₂CH₂); 1.40-1.56 (m, 2H, CH₃CH₂CH₂CH₂); 3.17 (dd, 2H, J=6.4Hz, J=13.5 Hz, CH₃CH₂CH₂CH₂); 3.83 (s, 3H, NCH₃); 5.93 (m, 1H,N(CH₃)—]—CHCHCHC—[); 6.68-6.75 (m, 1H, N(CH₃)]—CHCHCHC—[); 6.76-6.83 (m,1H, N(CH₃)]—CHCHCHC—[); 7.78-7.93 (m, 1H, NH).

II-23)

1-Methyl-1H-pyrrole-2-carboxylic acid butylmethylamide

δ (DMSO, 300 MHz)=0.88 (t, 3H, J=7.2 Hz, CH₃CH₂CH₂CH₂); 1.18-1.34 (m,2H, CH₃CH₂CH₂CH₂); 1.47-1.61 (m, 2H, CH₃CH₂CH₂CH₂); 3.01 (br. s, 3H,NCH₃); 3.44 (t, 2H, J=7.2 Hz, CH₃CH₂CH₂CH₂); 3.65 (s, 3H, NCH₃);5.97-6.03 (m, 1H, N(CH₃)—]—CHCHCHC—[); 6.25-6.32 (m, 1H,N(CH₃)]—CHCHCHC—[); 6.81-6.83 (m, 1H, N(CH₃)]—CHCHCHC—[).

II-24)

1-Methyl-1H-pyrrole-2-carboxylic acid (3-morpholin-4-yl-ethyl)-amide

δ (DMSO, 300 MHz)=2.38-2.45 (m, 6H, CONHCH₂CH₂, N(CH₂CH₂)₂O); 3.27-3.34(m, 2H, CONHCH₂CH₂); 3.54-3.62 (m, 4H, N(CH₂CH₂)₂O); 3.83 (s, 3H, NCH₃);5.98 (dd, 1H, J=2.6 Hz, J=3.7 Hz, N(CH₃)]—CHCHCHC—[); 6.69-6.71 (m, 1H,N(CH₃)]—CHCHCHC—[); 6.80-6.84 (m, 1H, N(CH₃)—]—CHCHCHC—[); 7.77-7.84 (m,1H, NH).

II-25)

1-Methyl-1H-pyrrole-2-carboxylic acid (3-morpholin-4-yl-propyl)-amide

δ (DMSO, 300 MHz)=1.58-1.68 (m, 2H, CONHCH₂CH₂CH₂); 2.23-2.42 (m, 6H,CONHCH₂CH₂CH₂, N(CH₂CH₂)₂O); 3.17 (d, 1H, J=6.8 Hz, CONHCH₂CH₂CH₂); 3.21(d, 1H, J=6.8 Hz, CONHCH₂CH₂CH₂); 3.35-3.60 (m, 4H, N(CH₂CH₂)₂O); 3.81(s, 3H, NCH₃); 5.96-6.03 (m, 1H, N(CH₃)]—CHCHCHC—[); 6.67-6.76 (m, 1H,N(CH₃)—]—CHCHCHC—[); 6.83-6.91 (m, 1H, N(CH₃)—]—CHCHCHC—[); 7.90-8.03(m, 1H, NH).

B)

General Synthesis Method for the Production of Compounds of the GeneralFormula III:

A solution of one equivalent of acetyl chloride in diethyl ether wasslowly added dropwise with stirring to the ice-cooled solution orsuspension of one equivalent of the particular compound of the generalformula V. Stirring of the reaction mixture was then continued for onehour at room temperature. A precipitate formed, which was removed bysuction filtration under nitrogen and then dried under an oil pumpvacuum. The resultant iminium salts of the general formula III were thenused in the following synthesis step without any further purification.

At variance with this synthesis method, compounds III-4 and III-5 werenot isolated, but instead directly used in the following synthesis step.

The compounds of the general formula III produced by the above generalsynthesis method are shown in Table 2 below: TABLE 2 Compound R¹ R* R³III-1 CH₃ CH₃ 4-fluorophenyl III-2 CH₃ CH₃ 4-bromophenyl III-3 CH₃ CH₃phenyl III-4 CH₃ CH₃ COOC₂H₅ III-5 —(CH₂)₅— COOC₂H₅C)

General Synthesis Method for the Production of Compounds According tothe Invention According to Examples 1-15:

The particular compounds of the general formulae II and III weredissolved in acetonitrile or compounds III-4 and III-5 were useddirectly as obtained according to B) and stirred overnight at roomtemperature (approx. 20-25° C.). The resultant solution was firstacidified with aqueous hydrochloric acid and nonbasic impurities wereextracted with diethyl ether. The aqueous phase was then combined withNa₂CO₃ solution and the particular example compound extracted withdiethyl ether. The resultant ethereal solution was dried over magnesiumsulfate. The particular compound according to the invention of Examples1-15 was then converted with the assistance of an ethanolic hydrogenchloride solution into the corresponding hydrochloride and isolated byfiltration. The resultant salt was then purified by washing withethanol.

The particular compounds of the general formulae II and III used for theproduction of example compounds according to the invention are shown inTable 3 below. TABLE 3 Compound of the general Compound of the generalExample formula II used formula III used 1 II-18 III-1 2 II-22 III-1 3II-5 III-1 4 II-18 III-2 5 II-22 III-2 6 II-5 III-2 7 II-6 III-2 8 II-1III-2 9 II-18 III-3 10 II-22 III-3 11 II-5 III-3 12 II-22 III-4 13 II-18III-4 14 II-22 III-5 15 II-18 III-5

The structure of the example compounds according to the invention was ineach case determined by ¹H-NMR spectroscopy. The values obtained are ineach case shown

Example 15-[Dimethylamino-(4-fluoro-phenyl)-methyl]-1-methyl-1H-pyrrole-2-carboxylicacid cyclohexylamide hydrochloride

¹H-NMR reveals two rotamers in the ratio of approx. 3:1. Only thesignals for the compound in excess are stated.

δ (DMSO, 600 MHz)=1.05-1.15 (m, 1H, NH]—CH(CH₂)₂(CH₂)₂CH₂—[);1.18-1.32(m, 5 H, NH]—CH(CH₂)₂(CH₂)₂CH₂—[); 1.65-1.85 (m, 4H,NH]—CH(CH₂)₂(CH₂)₂CH₂); 2.61(d, 1 H, J=4.5 Hz, N(CH₃)₂); 2.79 (d, 3H,J=4.5 Hz, N(CH₃)₂); 3.60-3.72 (m, 1H, NH]—CH(CH₂)₂(CH₂)₂CH₂—[); 3.84 (s,3H, NCH₃); 5.82 (d, 1H, J=9.1 Hz, CHN(CH₃)₂); 6.81 (d, 1 H, J=3.8 Hz,N(CH₃)]—CCHCHC—[); 6.86 (d, 1H, J=3.8 Hz, N(CH₃)]—CCHCHC—]); 7.24-7.34(m, 2H, p-FPh); 7.72-7.82 (m, 3H, p-FPh, NH); 11.64(3.1H, HCl).

Example 25-[Dimethylamino-(4-fluoro-phenyl)-methyl]-1-methyl-1H-pyrrole-2-carboxylicacid butylamide hydrochloride

¹H-NMR reveals two rotamers in the ratio of approx. 3:1. Only thesignals for the compound in excess are stated.

δ (DMSO, 600 MHz)=0.88 (t, 3H, J=7.5 Hz, CH₃CH₂CH₂CH₂); 1.25-1.34 (m,2H, CH₃CH₂CH₂CH₂); 1.40-1.48 (m, 2H, CH₃CH₂CH₂CH₂); 2.61 (d, 3H, J=4.5Hz, N(CH₃)₂); 2.79 (d, 3H, J=4.5 Hz, N(CH₃)₂); 3.10-3.20 (m, 2H,CH₃CH₂CH₂CH₂); 3.86 (s, 3H, NCH₃); 5.85 (d, 1H, J=9.1 Hz, CHN(CH₃)₂);6.79 (d, 1H, J=3.8 Hz, N(CH₃)]—CCHCHC—[); 6.91 (d, 1H, J=3.8 Hz,N(CH₃)]—CCHCHC—[); 7.24-7.32 (m, 2H, p-FPh); 7.75-7.83 (m, 2H, p-FPh);8.03-8.07 (m, 1H, NH); 11.76 (s, 1H, HCl).

Example 3{5-[Dimethylamino-(4-fluoro-phenyl)-methyl]-1-methyl-1H-pyrrol-2-yl}-pyrrolidin-1-yl-methanonehydrochloride

¹H-NMR reveals two rotamers in the ratio of approx. 4:1. Only thesignals for the compound in excess are stated.

δ (DMSO, 600 MHz)=1.72-1.91 (m, 4H, N(CH₂)₂(CH₂)₂); 2.61 (d, 3H, J=4.5Hz, N(CH₃)₂); 2.79 (d, 3H, J=4.5 Hz, N(CH₃)₂); 3.35-3.59 (m, 4H,N(CH₂)₂(CH₂)₂); 3.71 (s, 3H, NCH₃); 5.87 (d, 1H, J=9.1 Hz, CHN(CH₃)₂);6.57 (d, 1H, J=3.8 Hz, N(CH₃)]—CCHCHC—[); 6.95 (d, 1H, J=3.8 Hz,N(CH₃)]—CCHCHC—[); 7.27-7.33 (m, 2H, p-FPh); 7.78-7.88 (m, 2H, p-FPh);11.85 (s, 1H, HCl).

Example 45-[Dimethylamino-(4-bromo-phenyl)-methyl]-1-methyl-1H-pyrrole-2-carboxylicacid cyclohexylamide hydrochloride

¹H-NMR reveals two rotamers in the ratio of approx. 4.5:1. Only thesignals for the compound in excess are stated.

δ (DMSO, 600 MHz)=1.08-1.16 (m, 1H, NH]—CH(CH₂)₂(CH₂)₂CH₂—[); 1.19-1.34(m, 5H, NH]—CH(CH₂)₂(CH₂)₂CH₂—[); 1.53-1.64 (m, 1H,NH]—CH(CH₂)₂(CH₂)₂CH₂); 1.65-1.82 (m, 3H, NH]—CH(CH₂)₂(CH₂)₂CH₂); 2.63(d, 3H, J=4.5 Hz, N(CH₃)₂); 2.78 (d, 3H, J=4.5 Hz, N(CH₃)₂); 3.64-3.72(m, 1H, NH]—CH(CH₂)₂(CH₂)₂CH₂—[); 3.85 (s, 3H, NCH₃); 5.84 (d, 1H, J=9.1Hz, CHN(CH₃)₂); 6.81 (d, 1H, J=4.5 Hz, N(CH₃)]—CCHCHC—[); 6.87 (d, 1H,J=4.5 Hz, N(CH₃)]—CCHCHC—[); 7.63-7.67 (m, 2H, p-BrPh); 7.67-7.72 (m,2H, p-BrPh); 7.81 (d, 1H, J=8.3 Hz, NH); 11.81 (s, 1H, HCl).

Example 55-[Dimethylamino-(4-bromo-phenyl)-methyl]-1-methyl-1H-pyrrole-2-carboxylicacid butylamide hydrochloride

¹H-NMR reveals two rotamers in the ratio of approx. 3:1. Only thesignals for the compound in excess are stated.

δ (DMSO, 600 MHz)=0.88 (t, 3H, J=7.2 Hz, CH₃CH₂CH₂CH₂); 1.26-1.33 (m,2H, CH₃CH₂CH₂CH₂); 1.41-1.48 (m, 2H, CH₃CH₂CH₂CH₂); 2.63 (d, 3H, J=3.8Hz, N(CH₃)₂); 2.78 (d, 3H, J=4.5 Hz, N(CH₃)₂); 3.11-3.18 (m, 2H,CH₃CH₂CH₂CH₂); 3.86 (s, 3H, NCH₃); 5.85 (d, 1H, J=9.1 Hz, CHN(CH₃)₂);6.79 (d, 1H, J=3.8 Hz, N(CH₃)]—CCHCHC—[); 6.90 (d, 1H, J=3.8 Hz,N(CH₃)]—CCHCHC—[); 7.64-7.68 (m, 2H, p-BrPh); 7.68-7.73 (m, 2H, p-BrPh);8.03-8.08 (m, 1H, NH); 11.86 (s, 1H, HCl).

Example 6{5-[(4-Bromo-phenyl)-dimethylamino-methyl]-1-methyl-1H-pyrrol-2-yl)-pyrrolidin-1-yl-methanonehydrochloride

¹H-NMR reveals two rotamers in the ratio of approx. 4:1. Only thesignals for the compound in excess are stated.

δ (DMSO, 600 MHz)=1.74-1.92 (m, 4H, N(CH₂)₂(CH₂)₂); 2.63 (d, 3H, J=4.5Hz, N(CH₃)₂); 2.78 (d, 3H, J=4.5 Hz, N(CH₃)₂); 3.34-3.59 (m, 4H,N(CH₂)₂(CH₂)₂); 3.71 (s, 3H, NCH₃); 5.82-5.89 (m, 1H, CHN(CH₃)₂); 6.56(d, 1H, J=3.8 Hz, N(CH₃)]—CCHCHC—[); 6.92 (d, 1H, J=3.8 Hz,N(CH₃)]—CCHCHC—[); 7.66 (d, 2H, J=8.3 Hz, p-BrPh); 7.73 (d, 2H, J=8.3Hz, p-FPh); 11.86 (s, 1H, HCl).

Example 75-[(4-Bromo-phenyl)-dimethylamino-methyl]-1-methyl-1H-pyrrole-2-carboxylicacid phenethylamide hydrochloride

¹H-NMR reveals two rotamers in the ratio of approx. 3:1. Only thesignals for the compound in excess are stated.

δ (DMSO, 600 MHz)=2.59-2.61 (m, 2H, CH₂CH₂Ph); 2.67-2.71 (m, 2H,CH₂CH₂Ph); 2.75-2.79 (m, 6H, N(CH₃)₂); 3.85 (s, 3H, NCH₃); 5.82 (d, 1H,J=9.1 Hz, CHN(CH₃)₂); 6.77 (d, 1H, J=3.8 Hz, N(CH₃)]—CCHCHC—[); 6.86 (d,1H, J=3.8 Hz, N(CH₃)]—CCHCHC—[); 7.17-7.31 (m, 7H, p-BrPh, Ph);7.63-7.71 (m, 2H, p-BrPh); 8.19-8.23 (m, 1H, NH); 11.66 (s, 1H, HCl).

Example 8{5-[(4-Bromo-phenyl)-dimethylamino-methyl]-1-methyl-1H-pyrrol-2-yl}-morpholin-4-yl-methanonehydrochloride

δ (DMSO, 600 MHz)=2.59-2.69 (m, 4H, N(CH₂CH₂)₂O); 2.74-2.83 (m, 4H,N(CH₂CH₂)₂O); 3.51-3.59 (m, 6H, N(CH₃)₂); 3.63 (s, 3H, NCH₃); 5.78-5.85(m, 1H, CHN(CH₃)₂); 6.39 (d, 1H, J=3.8 Hz, N(CH₃)]—CCHCHC—[); 6.82 (d,1H, J=3.8 Hz, N(CH₃)]—CCHCHC—[); 7.65-7.71 (m, 4H, p-BrPh); 11.44 (s,1H, HCl).

Example 95-(Dimethylamino-phenyl-methyl)-1-methyl-1H-pyrrole-2-carboxylic acidcyclohexylamide hydrochloride

¹H-NMR reveals two rotamers in the ratio of approx. 4:1. Only thesignals for the compound in excess are stated.

δ (DMSO, 600 MHz)=1.08-1.15 (m, 1H, NH]—CH(CH₂)₂(CH₂)₂CH₂—[); 1.21-1.33(m, 5H, NH]—CH(CH₂)₂(CH₂)₂CH₂—[); 1.65-1.85 (m, 4H,NH]—CH(CH₂)₂(CH₂)₂CH₂); 2.61 (d, 3H, J=4.5 Hz, N(CH₃)₂); 2.78 (d, 3H,J=4.5 Hz, N(CH₃)₂); 3.61-3.70 (m, 1H, NH]—CH(CH₂)₂(CH₂)₂CH₂—[); 3.86 (s,3H, NCH₃); 5.80 (d, 1H, J=9.1 Hz, CHN(CH₃)₂); 6.81 (d, 1H, J=4.5 Hz,N(CH₃)]—CCHCHC—[); 6.89 (d, 1H, J=3.8 Hz, N(CH₃)]—CCHCHC—[); 7.36-7.41(m, 1H, Ph); 7.42-7.49 (m, 2H, Ph); 7.42-7.49 (m, 2H, Ph); 7.80 (d, 1H,J=8.3 Hz, NH); 11.74 (s, 1H, HCl).

Example 105-(Dimethylamino-phenyl-methyl)-1-methyl-1H-pyrrole-2-carboxylic acidbutylamide hydrochloride

¹H-NMR reveals two rotamers in the ratio of approx. 4:1. Only thesignals for the compound in excess are stated.

δ (DMSO, 600 MHz)=0.88 (t, 3H, J=7.6 Hz, CH₃CH₂CH₂CH₂); 1.26-1.33 (m,2H, CH₃CH₂CH₂CH₂); 1.40-1.48 (m, 2H, CH₃CH₂CH₂CH₂); 2.61 (d, 3H, J=4.5Hz, N(CH₃)₂); 2.78 (d, 3H, J=4.5 Hz, N(CH₃)₂); 3.10-3.20 (m, 2H,CH₃CH₂CH₂CH₂); 3.87(s, 3H, NCH₃); 5.80 (d, 1H, J=9.1 Hz, CHN(CH₃)₂);6.79 (d, 1H, J=3.8 Hz, N(CH₃)]—CCHCHC—[); 6.90 (d, 1H, J=3.8 Hz,N(CH₃)]—CCHCHC—[); 7.36-7.42 (m, 1H, Ph); 7.42-7.48 (m, 2H, Ph);7.69-7.78 (m, 2H, Ph); 8.01-8.07 (m, 1H, NH); 11.74(s, 1H, HCl).

Example 11[5-(Dimethylamino-phenyl-methyl)-1-methyl-1H-pyrrol-2-yl]-pyrrolidin-1-yl-methanonehydrochloride

¹H-NMR reveals two rotamers in the ratio of approx. 4:1. Only thesignals for the compound in excess are stated.

δ ([MSO, 600 MHz)=1.73-1.92 (m, 4H, N(CH₂)₂(CH₂)₂); 2.61 (d, 3H, J=4.5Hz, N(CH₃)₂); 2.79 (d, 3H, J=4.5 Hz, N(CH₃)₂); 3.34-3.61 (m, 4H,N(CH₂)₂(CH₂)₂); 3.73 (s, 3H, NCH₃); 5.81 (d, 1H, J=9.1 Hz, CHN(CH₃)₂);6.56 (d, 1H, J=3.8 Hz, N(CH₃)]—CCHCHC—[); 6.93 (d, 1H, J=3.8 Hz,N(CH₃)]—CCHCHC); 7.38-7.52 (m, 3H, Ph); 7.72-7.81 (m, 2H, Ph); 11.75 (s,1H, HCl).

Example 12(5-Butylcarbamoyl-1-methyl-1H-pyrrol-2-yl)-dimethylamino-acetic acidethyl ester hydrochloride

δ (DMSO, 600 MHz)=0.90 (t, 3H, J=7.5 Hz, CH₃CH₂CH₂CH₂); 1.22 (t, 3H,J=6.8 Hz, CH₃CH₂CO₂); 1.28-1.34 (m, 2H, CH₃CH₂CH₂CH₂); 1.44-1.49 (m, 2H,CH₃CH₂CH₂CH₂); 2.62 (br. s, 3H, N(CH₃)₂); 2.79 (br. s, 3H, N(CH₃)₂);3.12-3.22 (m, 2H, CH₃CH₂CH₂CH₂); 3.85 (s, 3H, NCH₃); 4.17-4.24 (m, 1H,CH₃CH₂CO₂); 4.24-4.32 (m, 1H, CH₃CH₂CO₂); 5.22-5.32 (m, 1H, CHN(CH₃)₂);6.79-6.84 (m, 1H, N(CH₃)]—CCHCHC—[); 7.11-7.17 (m, 1H, N(CH₃)]—CCHCHC);8.10-8.18 (m, 1H, NH); 10.59(s, 1H, HCl).

Example 13(5-Cyclohexylcarbamoyl-1-methyl-1H-pyrrol-2-yl)-dimethylamino-aceticacid ethyl ester hydrochloride

¹H-NMR reveals two rotamers in the ratio of approx. 4:1. Only thesignals for the compound in excess are stated.

δ (DMSO, 600 MHz)=1.06-1.15 (m, 1H, NH]—CH(CH₂)₂(CH₂)₂CH₂—[); 1.18 (t,3H, J=6.8 Hz, CH₃CH₂CO₂); 1.25-1.34 (m, 5H, NH]—CH(CH₂)₂(CH₂)₂CH₂—[);1.67-1.83 (m, 4H, NH]—CH(CH₂)₂(CH₂)₂CH₂); 2.60 (br. s, 3H, N(CH₃)₂);2.94 (br. s, 3H, N(CH₃)₂); 3.47-3.62 (m, 1H, NH]—CH(CH₂)₂(CH₂)₂CH₂—[);3.95 (s, 3H, NCH₃); 4.16-4.32 (m, 1H, CH₃CH₂CO₂); 5.60-5.71 (m, 1H,CHN(CH₃)₂); 6.30-6.40 (m, 1H, N(CH₃)]—CCHCHC—[); 6.79-6.85 (m, 1H,N(CH₃)]—CCHCHC—[); 7.89-7.99 (m, 1H, NH); 11.08(s, 1H, HCl).

Example 14(5-Butylcarbamoyl-1-methyl-1H-pyrrol-2-yl)-piperidin-1-yl-acetic acidethyl ester hydrochloride

δ (DMSO, 600 MHz)=0.90 (t, 3H, J=7.2 Hz, CH₃CH₂CH₂CH₂); 1.22 (t, 3H,J=7.2 Hz, CH₃CH₂CO₂); 1.26-1.38 (m, 2H, CH₃CH₂CH₂CH₂); 1.42-1.51 (m, 2H,CH₃CH₂CH₂CH₂); 1.63-1.71 (m, 2H, N(CH₂)₂(CH₂)₂CH₂); 1.72-1.90 (m, 4H,N(CH₂)₂(CH₂)₂CH₂); 2.89-3.02 (m, 2H, N(CH₂)₂(CH₂)₂CH₂); 3.10-3.24 (m,2H, N(CH₂)₂(CH₂)₂CH₂); 3.37-3.41 (m, 1H, CH₃CH₂CH₂CH₂); 3.42-3.49 (m,1H, CH₃CH₂CH₂CH₂); 3.84 (s, 3H, NCH₃); 4.15-4.22 (m, 1H, CH₃CH₂CO₂);4.25-4.32 (m, 1H, CH₃CH₂CO₂); 5.19-5.25 (m, 1H, CHN(CH₂)₂(CH₂)₂CH₂);6.77-6.83 (m, 1H, N(CH₃)]—CCHCHC—[); 7.09-7.15 (m, 1H, N(CH₃)]—CCHCHC);8.11-8.18 (m, 1H, NH); 10.38(s, 1H, HCl).

Example 15(5-Cyclohexylcarbamoyl-1-methyl-1H-pyrrol-2-yl)-piperidin-1-yl-aceticacid ethyl ester hydrochloride

δ (DMSO, 600 MHz)=1.05-1.16 (m, 1H, NH]—CH(CH₂)₂(CH₂)₂CH₂—[); 1.22 (t,3H, J=6.8 Hz, CH₃CH₂CO₂); 1.24-1.36 (m, 5H, NH]—CH(CH₂)₂(CH₂)₂CH₂—[);1.56-1.86 (m, 10H, NH]—CH(CH₂)₂(CH₂)₂CH₂, N(CH₂)₂(CH₂)₂CH₂,N(CH₂)₂(CH₂)₂CH₂); 2.63-2.72 (m, 1H, N(CH₂)₂(CH₂)₂CH₂); 2.91-2.98 (m,1H, N(CH₂)₂(CH₂)₂CH₂); 3.41-3.48 (m, 1H, N(CH₂)₂(CH₂)₂CH₂); 3.62-3.72(m, 1H, N(CH₂)₂(CH₂)₂CH₂); 3.84 (s, 3H, NCH₃); 4.15-4.20 (m, 1H,CH₃CH₂CO₂); 4.27-4.33 (m, 1H, CH₃CH₂CO₂); 5.21 (d, 1H, J=5.3 Hz,CHN(CH₂)₂(CH₂)₂CH₂); 6.81-6.86 (m, 1H, N(CH₃)]—CCHCHC—[); 7.08-7.14 (m,1H, N(CH₃)]—CCHCHC); 7.92 (d, 1H, J=7.5 Hz, NH); 10.22 (s, 1H, HCl).

Pharmacological Investigations:

a) Affinity for ORL-1 Receptor

The affinity of the 5-aminomethyl-1H-pyrrole-2-carboxylic acid amidesaccording to the invention for the ORL-1 receptor was determined asdescribed above. The value for a selected compound is shown in Table 4below. TABLE 4 Compound according to Human ORL-1 Example inhibition [%]9 23b) Affinity for μ receptor

The affinity of the 5-aminomethyl-1H-pyrrole-2-carboxylic acid amidesaccording to the invention for the μ receptor was determined asdescribed above. The values for some selected compounds are shown inTable 5 below. TABLE 5 Compound Human ORm according to Nal inhibitionHuman ORm Example [%] Nal Ki [μM] 1 62 0.16 2 49 0.36 4 80 0.79 5 62 * 765 1.0  9 76 * 11 33 ** not determinedc1) 5-HT Uptake Inhibition

5-HT uptake inhibition of the 5-aminomethyl-1H-pyrrole-2-carboxylic acidamides according to the invention was determined as described above. Thevalues for some selected compounds are shown in Table 6 below. TABLE 6Compound 5-HT uptake according to inhibition [%] Example conc. 10 1 57 252 4 72 5 57 6 51 7 93 8 79 11 54c2) Noradrenalin Reuptake Inhibition

The noradrenalin reuptake inhibition of the5-aminomethyl-1H-pyrrole-2-carboxylic acid amides according to theinvention was determined as described above. The values for someselected compounds are shown in Table 7 below. TABLE 7 CompoundNoradrenalin according to uptake inhibition Example [%] conc. 10 1 80 272 3 38 4 93 5 86 6 83 7 95 8 43 9 70 10 52

The foregoing description and examples have been set forth merely toillustrate the invention and are not intended to be limiting. Sincemodifications of the described embodiments incorporating the spirit andsubstance of the invention may occur to persons skilled in the art, theinvention should be construed broadly to include all variations withinthe scope of the appended claims and equivalents thereto.

1. A 5-aminomethyl-1H-pyrrole-2-carboxylic acid amide compound corresponding to formula I,

wherein, R¹ denotes hydrogen; a linear or branched, saturated or unsaturated, substituted or unsubstituted aliphatic residue; a saturated or unsaturated, substituted or unsubstituted cycloaliphatic residue which may comprise at least one heteroatom as a ring member and which may be attached via a substituted or unsubstituted alkylene group; a substituted or unsubstituted aryl or heteroaryl residue or a substituted or unsubstituted aryl or heteroaryl residue attached via a substituted or unsubstituted alkylene group, R² denotes hydrogen; a linear or branched, saturated or unsaturated, substituted or unsubstituted aliphatic residue; a saturated or unsaturated, substituted or unsubstituted cycloaliphatic residue which may comprise at least one heteroatom as a ring member and which may be attached via a substituted or unsubstituted alkylene group; a substituted or unsubstituted aryl or heteroaryl residue or a substituted or unsubstituted aryl or heteroaryl residue attached via a substituted or unsubstituted alkylene group, R¹ and R², together with the nitrogen atom joining them as a ring member, form a saturated or unsaturated, substituted or unsubstituted cycloaliphatic residue which may comprise at least one further heteroatom as a ring member, R³ denotes a substituted or unsubstituted aryl or heteroaryl residue, an ester group or a carboxy group, R⁴ and R⁵ may be identical or different, and denote hydrogen; a linear or branched, saturated or unsaturated, substituted or unsubstituted aliphatic residue; a saturated or unsaturated, substituted or unsubstituted cycloaliphatic residue which may comprise at least one heteroatom as a ring member and which may be attached via a substituted or unsubstituted alkylene group; a substituted or unsubstituted aryl or heteroaryl residue or a substituted or unsubstituted aryl or heteroaryl residue attached via a substituted or unsubstituted alkylene group, or R⁴ and R⁵, together with the nitrogen atom joining them as a ring member, form a saturated or unsaturated, substituted or unsubstituted cycloaliphatic residue which may comprise at least one further heteroatom as a ring member, and R⁶ denotes a linear or branched, saturated or unsaturated, substituted or unsubstituted aliphatic residue; a saturated or unsaturated, substituted or unsubstituted cycloaliphatic residue which may comprise at least one heteroatom as a ring member and which may be attached via a substituted or unsubstituted alkylene group; a substituted or unsubstituted aryl or heteroaryl residue or a substituted or unsubstituted aryl or heteroaryl residue attached via a substituted or unsubstituted alkylene group, or a physiologically acceptable salt thereof.
 2. The compound of claim 1, wherein said compound is present in the form of a free base.
 3. The compound of claim 1, wherein said compound is present in the form of an acid.
 4. The compound of claim 1, wherein said compound is present in the form of a pure enantiomer or pure diastereoisomer.
 5. The compound of claim 1, wherein said compound is present in the form of a mixture of stereoisomers.
 6. The compound of claim 1, wherein said compound is present in the form of a racemic mixture.
 7. The compound of claim 1, wherein said compound is present in the form of a solvate.
 8. The compound of claim 1, wherein said compound is present in the form of a hydrate.
 9. The compound of claim 1, wherein R¹ denotes hydrogen, a linear or branched, saturated or unsaturated, substituted or unsubstituted aliphatic C₁₋₆ residue; a saturated or unsaturated, substituted or unsubstituted cycloaliphatic C₃₋₈ residue which may comprise at least one heteroatom as a ring member and may be attached via a substituted or unsubstituted C₁₋₃ alkylene group; a substituted or unsubstituted, five- or six-membered aryl or heteroaryl residue or a substituted or unsubstituted, five- or six-membered aryl or heteroaryl residue attached via a substituted or unsubstituted C₁₋₃ alkylene group.
 10. The compound of claim 9, wherein the substituted or unsubstituted C₁₋₃ alkylene group which attaches the substituted or unsubstituted five- or six-membered aryl or heteroaryl residue is a linear or branched, saturated aliphatic C₁₋₃ residue.
 11. The compound of claim 10, wherein the substituted or unsubstituted C₁₋₃ alkylene group which attaches the substituted or unsubstituted five- or six-membered aryl or heteroaryl residue is a methyl group.
 12. The compound of claim 1, wherein R² denotes a linear or branched, saturated or unsaturated, substituted or unsubstituted aliphatic C₁₋₆ residue; a saturated or unsaturated, substituted or unsubstituted cycloaliphatic C₃₋₈ residue which may comprise at least one heteroatom as a ring member and may be attached via a substituted or unsubstituted C₁₋₃ alkylene group; a substituted or unsubstituted five- or six-membered aryl or heteroaryl residue or a substituted or unsubstituted five- or six-membered aryl or heteroaryl residue attached via a substituted or unsubstituted C₁₋₃ alkylene group.
 13. The compound of claim 12, wherein the substituted or unsubstituted C₁₋₃ alkylene group which attaches the substituted or unsubstituted five- or six-membered aryl or heteroaryl residue is a linear or branched, saturated aliphatic C₁₋₃ residue.
 14. The compound of claim 13, wherein the substituted or unsubstituted C₁₋₃ alkylene group which attaches the substituted or unsubstituted five- or six-membered aryl or heteroaryl residue is a methyl group.
 15. The compound of claim 1, wherein R¹ and R², together with the nitrogen atom joining them as a ring member, form a saturated or unsaturated, substituted or unsubstituted, five- or six-membered cycloaliphatic residue, which may comprise at least one further heteroatom selected from the group consisting of N, O and S as a ring member.
 16. The compound of claim 1, wherein R¹ and R², together with the nitrogen atom joining them as a ring member, form a saturated, five- or six-membered cycloaliphatic residue which comprises oxygen as a further ring member.
 17. The compound of claim 1, wherein R¹ and R² together denote a (CH₂)₄, (CH₂)₅ or (CH₂)₂—O—(CH₂)₂ residue which, with the nitrogen atom joining them as a ring member, forms a heterocycle.
 18. The compound of claim 1, wherein R³ denotes a substituted or unsubstituted, five- or six-membered aryl or heteroaryl residue or an aryl ester, heteroaryl ester or alkyl ester group.
 19. The compound of claim 18, wherein R³ denotes a substituted or unsubstituted phenyl residue or an alkyl ester group with C₁₋₃ in the alkyl moiety.
 20. The compound of claim 18, wherein R³ denotes an alkyl ester group with C₁₋₂ in the alkyl moiety.
 21. The compound of claim 1, wherein R⁴ and R⁵, may be the same or different, and denote hydrogen; a linear or branched, saturated or unsaturated, substituted or unsubstituted aliphatic C₁₋₆ residue; a saturated or unsaturated, substituted or unsubstituted cycloaliphatic C₃₋₈ residue which may comprise at least one heteroatom as a ring member and which may be attached via an substituted or unsubstituted C₁₋₃ alkylene group; a substituted or unsubstituted, five- or six-membered aryl or heteroaryl residue or a substituted or unsubstituted, five- or six-membered aryl or heteroaryl residue attached via an substituted or unsubstituted C₁₋₃ alkylene group.
 22. The compound of claim 1, wherein R⁴ and R⁵, together with the nitrogen atom joining them as a ring member, form a saturated or unsaturated, substituted or unsubstituted, five-, six- or seven-membered cycloaliphatic residue, which may comprise at least one further heteroatom selected from the group consisting of N, O and S as a ring member.
 23. The compound of claim 1, wherein R⁴ and R⁵, together with the nitrogen atom joining them as a ring member, form a saturated, five- or six-membered cycloaliphatic residue which comprises oxygen as a further ring member.
 24. The compound of claim 1, wherein R⁴ and R⁵, together denote a (CH₂)₄, (CH₂)₅ or (CH₂)₂—O—(CH₂)₂ residue which, together with the nitrogen atom joining them as a ring member, forms a heterocycle.
 25. The compound of claim 1, wherein R⁶ denotes a linear or branched, saturated or unsaturated, substituted or unsubstituted aliphatic C₁₋₆ residue; a saturated or unsaturated, substituted or unsubstituted cycloaliphatic C₃₋₈ residue which may comprise at least one heteroatom as a ring member and which may be attached via a substituted or unsubstituted C₁₋₃ alkylene group; an substituted or unsubstituted, five- or six-membered aryl or heteroaryl residue, a substituted or unsubstituted, five- or six-membered aryl or heteroaryl residue attached via a substituted or unsubstituted C₁₋₃ alkylene group.
 26. The compound of claim 25, wherein the substituted or unsubstituted C₁₋₃ alkylene group which attaches the substituted or unsubstituted five- or six-membered aryl or heteroaryl residue is a linear or branched, saturated aliphatic C₁₋₃ residue.
 27. The compound of claim 25, wherein the substituted or unsubstituted C₁₋₃ alkylene group which attaches the five- or six-membered aryl or heteroaryl residue is a methyl residue.
 28. The compound of claim 1, wherein said compound is selected from the group consisting of: 5-[dimethylamino-(4-fluoro-phenyl)-methyl]-1H-methyl-1H-pyrrole-2-carboxylic acid cyclohexylamide, 5-[dimethylamino-(4-fluoro-phenyl)-methyl]-1-methyl-1H-pyrrole-2-carboxylic acid butylamide, {5-[dimethylamino-(4-fluoro-phenyl)-methyl]-1H-methyl-1H-pyrrol-2-yl}-pyrrolidin-1-yl-methanone, 5-[dimethylamino-(4-bromo-phenyl)-methyl]-1-methyl-1H-pyrrole-2-carboxylic acid cyclohexylamide, 5-[dimethylamino-(4-bromo-phenyl)-methyl]-1-methyl-1H-pyrrole-2-carboxylic acid butylamide, {5-[(4-bromo-phenyl)-dimethylamino-methyl]-1H-methyl-1H-pyrrol-2-yl}-pyrrolidin-1-yl-methanone, 5-[(4-bromo-phenyl)-dimethylamino-methyl]-1H-methyl-1H-pyrrole-2-carboxylic acid phenethyl-amide, {5-[(4-bromo-phenyl)-dimethylamino-methyl]-1-methyl-1H-pyrrol-2-yl}-morpholin-4-yl-methanone, 5-(dimethylamino-phenyl-methyl)-1-methyl-1H-pyrrole-2-carboxylic acid cyclohexylamide, 5-(dimethylamino-phenyl-methyl)-1-methyl-1H-pyrrole-2-carboxylic acid butylamide, [5-(dimethylamino-phenyl-methyl)-1-methyl-1H-pyrrol-2-yl]-pyrrolidin-1-yl-methanone, (5-butylcarbamoyl-1-methyl-1H-pyrrol-2-yl)-dimethylamino-acetic acid ethyl ester, (5-cyclohexylcarbamoyl-1-methyl-1H-pyrrol-2-yl)-dimethylamino-acetic acid ethyl ester, (5-butylcarbamoyl-1-methyl-1H-pyrrol-2-yl)-piperidin-1-yl-acetic acid ethyl ester and (5-cyclohexylcarbamoyl-1-methyl-1H-pyrrol-2-yl)-piperidin-1-yl-acetic acid ethyl ester.
 29. A process for producing a 5-aminomethyl-1H-pyrrole-2-carboxylic acid amide compound according to claim 1, comprising reacting a substituted 1H-pyrrole-2-carboxylic acid amide corresponding to formula II

with an iminium salt corresponding to formula III,

wherein A⁻ denotes a suitable anion.
 30. The process of claim 29, wherein A⁻ is selected from the group consisting of Cl⁻, AlCl₄ ⁻, Br⁻, I⁻ or CF₃—SO₃ ⁻ (triflate anion).
 31. The process of claim 29, further comprising the step of isolating the compound according to claim
 1. 32. A pharmaceutical preparation comprising as an active ingredient, at least one substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amide compound according to claim 1, and at least one physiologically acceptable auxiliary substance.
 33. The pharmaceutical preparation of claim 32, said pharmaceutical preparation comprising an amount of a substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amide compound pharmaceutically effective for alleviating pain.
 34. The pharmaceutical preparation of claim 33, wherein said pain is selected from the group consisting of acute, chronic or neuropathic pain.
 35. The pharmaceutical preparation of claim 32, said pharmaceutical preparation comprising an amount of a substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amide compound pharmaceutically effective for treatment or inhibition of a condition selected from the group consisting of withdrawal symptoms, respiratory diseases, sexual dysfunction, erectile dysfunction, depression, pruritus, tinnitus, anorexia, urinary incontinence, suppression of the urinary reflex, diarrhoea, water retention conditions, cardiovascular disorders, diuresis, epilepsy, neurodegenerative diseases, memory disorders, anxiolysis or for inhibiting noradrenalin uptake, inhibiting 5-hydroxytryptamine (5-HT) uptake, regulating the ORL-1 receptor, regulating the electrolyte balance, influencing the cardiovascular system, modulating locomotor activity, for reducing the addictive potential of opioids or regulating food intake.
 36. The pharmaceutical preparation of claim 35, wherein said neurodegenerative disease is Parkinson's disease, Huntington's chorea or Alzheimer's disease.
 37. The pharmaceutical preparation of claim 35, wherein said amount of a substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amide compound is pharmaceutically effective for stimulating food intake or for vasodilating the arteries.
 38. A method of alleviating pain in a mammal, said method comprising administering to said mammal an effective pain alleviating amount of a 5-aminomethyl-1H-pyrrole-2-carboxylic acid amide compound of claim
 1. 39. A method of treating or inhibiting a condition selected from the group consisting of withdrawal symptoms, memory disorders, neurodegenerative diseases, epilepsy, cardiovascular disorders, water retention conditions, diarrhea, urinary incontinence, anorexia, tinnitus, pruritus, depression, sexual dysfunction, respiratory diseases, or for anxiolysis, for diuresis, for suppression of the urinary reflex, for regulating, preferably stimulating, food intake, for reducing the addictive potential of opioids, preferably of morphine, for modulating locomotor activity, for influencing the cardiovascular system, for regulating the ORL-1 receptor, for inhibiting noradrenalin uptake or for inhibiting 5-hydroxytryptamine (5-HT) uptake comprising administering a pharmaceutically effective amount of a compound according to claim
 1. 